This invention relates to a process for producing a sequential polyamino acid resin having a high degree of polymerization and a constant amino acid sequence as repeating unit in the resin.
As a synthetic method of ordinary polyamino acids, there is well known a method which comprises polymerizing an amino acid-N-carboxy anhydride (NCA). However, strictly speaking, no sequential polyamino acid having a constant amino acid sequence can be obtained even when different two amino acid-N-carboxy anhydrides, amino acid-NCA-1 and amino acid-NCA-2 are copolymerized by the above-mentioned method. This is because in general, NCA-1 and NCA-2 are different in reactivity and hence the ratio of the amino acid-1 to the amino acid-2 in the resulting polymer changes depending on proportions of amino acid-NCAs, which results in producing a random (non-sequential) copolymer.
In order to remove the defects described above, there have been proposed many methods which comprise effecting polymerization by using, as a monomer, an activated peptide having desired amino acid sequence. For example, it has been reported that poly(L-prolyl-L-leucyl-glycine) is obtained by a method which comprises polymerizing L-prolyl-L-leucyl-glycine.hydrochloride in the presence of dicyclohexylcarbodiimide and a base (hereinafter referred to as "DCC method" or a method which comprises polymerizing a chlorinated phenyl ester of L-prolyl-L-leucyl-glycine.trifluoroacetate in the presence of an organic amine (hereinafter referred to as "active ester method") [H. Kitaoka, S. Sakakibara, H. Tani: Bull. Chem. Soc., Japan, 31, 802(1958) and Japanese Patent Appln Kokai (Laid-Open) No. 137495/77]. Further, there has also been reported a comparison made by applying all the methods comprising mutually combining amino acids (coupling methods of amino acids) to peptides as monomer, investigating the polymerization reaction of the peptides, and comparing merits and demerits of the methods as polymerization methods (B. J. Johnson: J. Pharm. Sci., 63, 313 (1974), and "Chemistry and Biochemistry of Amino Acids, Peptides and Proteins" edited by B. Weinstein, vol. 4, p. 29 Marcel Deckker Inc., New York).
However, according to any of the methods described above, the resulting polymer has an average molecular weight of several thousands or less, and its inherent viscosity .sup..eta. inh (C=0.5) is only 0.1 to 0.2 as measured in dichloroacetic acid at a concentration of 0.5 g/dl.
On the other hand, it is generally known that when polymerization is carried out by using a dipeptide as a monomer, dimers or trimers formed in the course of the polymerization easily cause cyclization reaction to give cyclic peptides. Therefore, it is generally said that a high molecular weight is difficult to attain by polymerizing a dipeptide. In fact, no polymer can substantially be obtained by carrying out polymerization by the above-mentioned method.
Owing to these circumstances, it is generally accepted in the industrial world and the academic world that no polyamino acid having a high molecular weight can be obtained by polymerizing a peptide, in particular, dipeptide as a monomer (see the same literature as described above).